1. Field of the Invention
This invention relates to heterocyclic amino substituted heteroaryl fused pyridines, and more specifically to such compounds that selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness. The interaction of heterocyclic amino substituted heteroaryl fused pyridines of the invention with a GABA binding site, the benzodiazepines (BDZ) receptor, is described. This interaction results in the pharmacological activities of these compounds.
2. Description of the Related Art
xcex3-Aminobutyric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 40 years have elapsed since its presence in the brain was demonstrated (Roberts and Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA.
The 1,4-Benzodiazepines, such as diazepam, continue to be among the most widely used drugs in the world as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists.
The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into xcex1, xcex2, xcex3, xcex4, xcex5, and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The xcex3 subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.
With the discovery of the xe2x80x9creceptorxe2x80x9d for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety).
This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I: 
wherein:
the C ring represents a thiophene, pyridine, pyrazine, pyridazine, or pyrimidine ring, each of which is optionally mono- or disubstituted with lower alkyl, C1-C6 alkoxy, hydroxy, halogen, amino, mono- or di(C1-C6) alkylamino, or trifluoromethyl;
n is 0 or an integer of from 1-3;
X is CH, nitrogen, or oxygen;
Z is an electron pair when X is oxygen;
Z is hydrogen;
Z is aryl or heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from lower alkyl, lower alkoxy, amino, mono- or di(C1-C6)alkylamlno, or halogen; or 
xe2x80x83where
Z is
Y is oxygen or sulfur;
R is lower alkyl, hydroxy, lower alkoxy, hydroxyalkyl, or aminoalkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl;
R is aryl or heteroaryl each of which is mono or disubstituted independently with halogen, thio, hydroxyl, lower alkyl, lower alkoxy, amino or mono- or di(C1-C6)alkylamino;
R is amino, optionally substituted with one or two groups independently selected from
lower alkyl, hydroxyalkyl, C3-C7 cycloalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, or amidoalkyl;
heteroaryl, arylalkyl or heteroarylalkyl, optionally substituted with one or two groups independently selected from halogen, thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or
a C3-C7 carbocyclic group having, where up to two of which atoms of the carbocyclic group are optionally hetero atoms selected from oxygen and nitrogen and where any atom of the carbocyclic group is optionally substituted with halogen, lower alkyl or lower alkoxy; or
R is a carbocyclic group having from 3-7 members, where up to three of which members are optionally hetero atoms selected from oxygen and nitrogen and where any member of the carbocyclic group is optionally substituted with halogen, lower alkyl, or lower alkoxy;
A and B are the same or different and represent hydrogen or lower alkyl; and
W is aryl or heteroaryl, each of which may be mono-, or di-, or trisubstituted independently with halogen, hydroxyl, lower alkyl, lower alkoxy, amino, mono- or di(C1-C6)alkylamino, trifluoromethyl or nitro.
These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. In other words, while the compounds of the invention all interact with GABAa brain receptors, they do not display identical physiological activity. Thus, these compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. For example, these compounds can be used to treat overdoses of benzodiazepine-type drugs as they would competitively bind to the benzodiazepine receptor.
The novel compounds encompassed by the instant invention can be described by general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
In addition, the present invention also encompasses compounds of Formula IIa and IIb 
wherein A, B, W, X, Z, and n are as defined above for Formula I; and
Ra and Rb independently represent hydrogen, lower alkyl, C1-C6 alkoxy, hydroxy, halogen, amino, mono- or di(C1-C6)alkylamino, or trifluoromethyl.
Preferred compounds of Formula IIa and IIb are Ra and Rb are hydrogen, and a where W is phenyl or 2-, 3-, or 4-pyridyl, each of which is optionally mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy. Other preferred compounds of Formula IIa and IIb are those where X is CH and Z is or 2-imidazolyl, or 1,2,4-triazol-3-yl,
Other preferred compounds of the invention are those of Formula II where n is 2 or 3.
Other preferred compounds of Formula IIa and IIb are where A and B are hydrogen or methyl.
Preferred Z groups in Formulae IIa and IIb include Z-1, Z-2, Z-3, Z-4, Z-5, Z-6, Z-7, Z-8, and Z-9 groups. 
where Rz, and Ry are independently hydrogen, C1-C6 alkyl, 2-, 3-, or 4-pyridylmethyl, C3-C7, preferably C4-C6, cycloalkyl, C1-C6 alkoxy(C1-C6)alkyl, or 2- or 3-tetrahydrofuranyl(C1-C6)alkyl. Preferred C1-C6 alkoxy(C1-C6)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl. Preferred tetrahydrofuranyl-(C1-C6)alkyl groups are tetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups are those where one and only one of Rz and Ry is hydrogen. 
where E is a bond or C1-C6 alkylene, each of Rp and Rpxe2x80x2 are independently hydroxy, halogen, C1-C6 alkyl, or C1-C6 alkoxy. Preferred Rp groups are fluoro, more preferably 4-fluoro, and chloro. Preferred Rpxe2x80x2 groups are hydrogen, C1-C2 alkoxy, C1-C2 alkyl, fluoro, more preferably 4-fluoro, and chloro. Preferred E groups are a bond and C2 alkylene. 
where G is 2-, 3-, or 4-pyridyl, each of which is optionally mono- or disubstituted with C1-C6 alkyl, Cl-C6 alkoxy, or halogen. 
where Rz and Ry are independently hydrogen, C1-C6 alkyl, 2-, 3-, or 4-pyridylmethyl, C3-C7, preferably C4-C6, cycloalkyl, C1-C6 alkoxy(C1-C6) alkyl, 2-, or 3-tetrahydrofuranyl(C1-C6)alkyl. Preferred C1-C6 alkoxy(C1-C6)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl. Preferred tetrahydrofuranyl(C1-C6)alkyl groups are tetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups are those where one and only one of Rz and Ry is hydrogen. 
where Re is hydrogen or C1-C6 alkyl. Preferred Re groups in Z-7 are hydrogen atoms. 
where each Re is independently hydrogen or C1-C6 alkyl. Preferred Re groups in Z-8 are hydrogen and methyl. 
where R is C1-C6 alkyl.
The present invention also enc ompasses compounds of Formula IIIa and Formula IIIb: 
wherein W, X and Z are as defined above for Formula I; and Ra is hydrogen, lower alkyl, C1-C6 alkoxy, hydroxy, halogen, amino, mono- or di(C1-C6)alkylamino, or trifluoromethyl.
Preferred compounds of Formula IIIa and IIIb are where W is phenyl or 2-, 3-, or 4-pyridyl, each of which is optionally mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy.
Preferred Z groups in Formulae IIIa and IIIb include Z-1, Z-2, Z-3, Z-4, Z-5, Z-6, Z-7, Z-8, and Z-9 groups. 
where Rz and Ry are independently hydrogen, C1-C6 alkyl, 2-, 3-, or 4-pyridylmethyl, C3-C7, preferably C4-C6, cycloalkyl, C1-C6 alkoxy(C1-C6)alkyl, or 2- or 3-tetrahydrofuranyl(C1-C6)alkyl. Preferred C1-C6 alkoxy(C1-C6)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl. Preferred tetrahydrofuranyl-(C1-C6)alkyl groups are tetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups are those where one and only one of Rz and Ry is hydrogen. 
where E is a bond or C1-C6 alkylene, each of Rp and Rpxe2x80x2 are independently hydroxy, halogen, C1-C6 alkyl, or C1-C6 alkoxy. Preferred Rp groups are fluoro, more preferably 4-fluoro, and chloro. Preferred Rpxe2x80x2 groups are hydrogen, C1-C2 alkoxy, C1-C2 alkyl, fluoro, more preferably 4-fluoro, and chloro. Preferred E groups are a bond and C2 alkylene. 
where G is 2-, 3-, or 4-pyridyl, each of which is optionally mono- or disubstituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen. 
where Rz and Ry are independently hydrogen, C1-C6 alkyl, 2-, 3-, or 4-pyridylmethyl, C3-C7, preferably C4-C6, cycloalkyl, C1-C6 alkoxy(C1-C6)alkyl, 2-, or 3-tetrahydrofuranyl(C1-C6)alkyl. Preferred C1-C6 alkoxy(C1-C6)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl. Preferred tetrahydrofuranyl(C1-C6)alkyl groups are tetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups are those where one and only one of Rz and Ry is hydrogen. 
where Re is hydrogen or C1-C6 alkyl. Preferred Re groups in Z-7 are hydrogen atoms. 
where each Re is independently hydrogen or C1-C6 alkyl. Preferred Re groups in Z-8 are hydrogen and methyl. 
where R is C1-C6 alkyl.
The present invention also encompasses compounds of Formula IV: 
wherein W, X, and Z are as defined above in Formula I; and
A, B, C, and D are independently CR1 or nitrogen, provided that no more than two of A, B, C, and D are nitrogen simultaneously; and
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl.
Preferred compounds of Formula IV are where W is phenyl or 2-, 3-, or 4-pyridyl each of which is optionally mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy.
Still other preferred compounds of Formula IV are those where A is nitrogen and B, C, and D are hydrogen.
Preferred Z groups in Formula IV include Z-1, Z-2, Z-3, Z-4, Z-5, Z-6, Z-7, Z-8, and Z-9 groups. 
where Rz and Ry are independently hydrogen, C1-C6 alkyl, 2-, 3-, or 4-pyridylmethyl, C3-C7, preferably C4-C6, cycloalkyl, C1-C6 alkoxy(C1-C6)alkyl, or 2- or 3-tetrahydrofuranyl(C1-C6)alkyl. Preferred C1-C6 alkoxy(C1-C6)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl. Preferred tetrahydrofuranyl-(C1-C6)alkyl groups are tetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-1 groups are those where one and only one of Rz and Ry is hydrogen. 
where E is a bond or C1-C6 alkylene, each of Rp and Rpxe2x80x2 are independently hydroxy, halogen, C1-C6 alkyl, or C1-C6 alkoxy. Preferred Rp groups are fluoro, more preferably 4-fluoro, and chloro. Preferred Rpxe2x80x2 groups are hydrogen, C1-C2 alkoxy, C1-C2 alkyl, fluoro, more preferably 4-fluoro, and chloro. Preferred E groups are a bond and C2 alkylene. 
where G is 2-, 3-, or 4-pyridyl, each of which is optionally mono- or disubstituted with C1-C6 alkyl, C1-C6, alkoxy, or halogen. 
where Rz and Ry are independently hydrogen, C1-C6 alkyl, 2-, 3-, or 4-pyridylmethyl, C3-C7, preferably C4-C6, cycloalkyl, C1-C6 alkoxy(C1-C6)alkyl, 2-, or 3-tetrahydrofuranyl(C1-C6)alkyl. Preferred C1-C6 alkoxy(C1-C6)alkyl groups are 2-methoxyethyl and 2-ethoxyethyl. Preferred tetrahydrofuranyl(C1-C6)alkyl groups are tetrahydrofuran-2-ylmethyl groups. Particularly preferred Z-6 groups are those where one and only one of Rz and Ry is hydrogen. 
where Re is hydrogen or C1-C6 alkyl. Preferred Re groups in Z-7 are hydrogen atoms. 
where each Re is independently hydrogen or C1-C6 alkyl. Preferred Re groups in Z-8 are hydrogen and methyl. 
where R is C1-C6 alkyl.
Preferred compounds of the invention are encompassed by the following formulae: 
where W, X, and Y are as defined above in Formula I;
Ra is hydrogen, lower alkyl, C1-C6 alkoxy, hydroxy, halogen, amino, mono- or di(C1-C6)alkylamino, or trifluoromethyl; and
R2 and R3 are the same or different and represent
hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalky, or amidoalkyl;
aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which may be mono or disubstituted independently on the aryl group with halogen, thio, hydroxyl, lower alkyl, lower alkoxy, or amino; or
a C3-C7 carbocyclic or C3-C7 carbocyclic (C1-C6) alkyl group having from 3-7 members, where up to two of which members are optionally hetero atoms selected from oxygen and nitrogen and where any member of the carbocyclic group is optionally substituted with halogen, lower alkyl or lower alkoxy.
More preferred compounds of Formula Va and Vb are those where R2 is hydrogen and where W is aryl or heteroaryl mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy.
Other preferred compounds are represented by Formula VI. 
where W, and X are as defined above in Formula I and wherein:
A, B, C, and D are independently CR1 or nitrogen, provided that at least one but not more than two of A, B, C, and D are nitrogen simultaneously;
R1 is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, thio, or arylalkyl; and
R2 and R3 are the same or different and represent
hydrogen, lower alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalky, or amidoalkyl;
aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which may be mono or disubstituted independently on the aryl group with halogen, thio, hydroxyl, lower alkyl, lower alkoxy, or amino, or
a carbocyclic or carbocyclic(C1-C6)alkyl group having from 3-7 members in the carbocyclic portion, where up to two of which members are optionally hetero atoms selected from oxygen and nitrogen and where any member of the carbocyclic group is optionally substituted with halogen, lower alkyl or lower alkoxy.
More preferred compounds of Formula VI are where W is phenyl or 2-, 3-, or 4-pyridyl each of which is optionally mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy; where A is nitrogen and B, C, and D are hydrogen; and where R2 is hydrogen and R3 is hydrogen or lower alkyl.
Still other preferred compounds of the invention are represented by Formula VIIa and VIIb. 
where W and X are as above in Formula I and wherein
n is the integer 2 or 3;
Z is an electron pair when X is oxygen;
Z is hydrogen;
Z is aryl optionally substituted with one or two groups selected from lower alkyl, lower alkoxy, or halogen; or 
xe2x80x83where
Z is
Y oxygen or sulfur;
R is amino, optionally substituted with one or two groups selected from lower alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, hydroxy, aminoalkyl, amidoalkyl, heteroaryl.
More preferred compounds of Formula VIIa and VIIb are where where Y is oxygen and W is aryl or heteroaryl mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy.
The present invention also encompasses compounds of Formula VIIIa and Formula VIIIb: 
wherein W and X are as defined above for Formula I;
Rx is hydrogen, lower alkyl, C1-C6 alkoxy, hydroxy, halogen, amino, mono- or di(C1-C6)alkylamino, or trifluoromethyl;
A is nitrogen or CH; and
Rx is hydrogen, lower alkyl, hydroxy, lower alkoxy, hydroxyalkyl, or aminoalkyl, or mono- or di(C1-C6)alkylamino (C1-C6)alkyl.
Preferred compounds of Formula VIIIa and VIIIb are where W is phenyl or 2-, 3-, or 4-pyridyl, each of which is optionally mono or disubstituted independently with halogen, hydroxyl, lower alkyl, or lower alkoxy. Other preferred compounds of Formulae VIIIa and b are those where X is CH and A is CH. More preferred compounds of Formula VIIIa and b where A is CH are those where Rx is hydrogen, methyl or ethyl. Particularly preferred compounds of Formulae VIIIa and b where A is CH are those where W is phenyl optionally substituted with one or two groups selected from halogen, preferably fluoro and chloro, methyl, ethyl, or amino.
Still other preferred compounds of Formulae VIIIa and b are those where X is CH and A is nitrogen. More preferred compounds of Formula VIIIa and b where A is nitrogen are those where Rx is hydrogen, methyl or ethyl. Particularly preferred compounds of Formulae VIIIa and b where A is nitrogen are those where W is phenyl optionally substituted with one or two groups selected from halogen, preferably fluoro and chloro, methyl, ethyl, or amino.
By xe2x80x9calkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
By xe2x80x9calkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By the term xe2x80x9chalogenxe2x80x9d in the present invention is meant fluorine, bromine, chlorine, and iodine. Preferred halogens are fluorine, bromine, and chlorine.
By heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl, benzimidazolyl, benzoxazolyl. Preferred heteroaryl groups are pyrimidinyl, pyridyl, imidazolyl, naphthyridinyl, and benzimidazolyl groups that are optionally substituted as described herein.
The heteroaryl groups of the invention may be substituted with up to four groups selected from, for example, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, halogen, thio, hydroxy, amino, mono- or di(C1-C6)alkylamino, C3-C7 cycloalkyl, alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, and amidoalkyl. Other heteroaryl substituents include, for example, phenyl, pyridyl, pyrimidiyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, and pyrrolidinyl.
By 1H-1,4-Diazepine is meant the structure 
By aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy. Preferred aryl groups are phenyl and napthyl groups that are optionally substituted as described herein.
The aryl groups of the invention may be substituted with up to four groups selected from, for example, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, halogen, thio, hydroxy, amino, mono- or di(C1-C6)alkylamino, C3-C7 cycloalkyl, alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, and amidoalkyl. Other aryl substituents include, for example, phenyl, pyridyl, pyrimidiyl, imidazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, and pyrrolidinyl.
Representative C3-C7 carbocyclic or C3-C7 carbocyclic(C1-C6)alkyl groups that include one or two oxygen or nitrogen atoms are, for example, morpholino, pyrrolo, imidazolyl, piperidinyl, piperazinyl, pyrazinyl, pyranyl, tetrahydropyanyl, pyrrolidinyl, 1H-1,4-diazepinyl, and pyrrolinyl. These groups are optionally substituted with one or two groups, preferably one group, selected from halogen, lower alkyl and lower alkoxy.
Representative compounds of the invention are shown below in Table 1.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid and base addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
The compounds of Formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. guch materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions with a mullet-dose of the drug so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water.
The compounds of the invention may be prepared using the synthetic routes outlined in the following schemes. 
where A, B, the C ring, W, Y, R, R2, R3 and n are as defined above in Formula I.
Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. For example, certain groups, e.g., nitrogen and hydroxy, may require protection during the synthesis.
As shown in Scheme I, an aniline is reacted with a suitable xcex2-keto ester in the presence of an acid, such as, for example, P-toluenesulfonic acid, to form a 4-hydroxypyridine which is subsequently converted to the 4-chloropyridine upon treatment with a nucleophilic halogenating reagent such phosphorus oxychloride. The resulting chloride is reacted with the desired 1,4-diheterocarbocycle, such as a piperazine or 1,4-diazaperhydropine at elevated temperatures to form the N-alkylated product. The piperdine can then be further alkylated with a desired isocyanate or isothiocyanate, such as, for example, methyl isocyanate, to form the target compound.
As shown in Scheme II, a 4-chloropyridine is reacted with a reagent such as ethyl 4-piperdinecarboxylate at elevated temperatures to form the N-alkylated ester. The ester is treated with an amine, such as methylamine, in the presence of a base such as sodium hydroxide to form the resulting amide.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.
The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.